Apoptosis, or programmed cell death (PCD), is of fundamental importance to biological processes including embryogenesis, maintenance of tissue homeostasis, normal cellular development of multicellular organisms, elimination of virus-infected cells, and the development of the immune system (Ellis et al. (1991) Ann. Rev. Cell Biol. 7:663-698). It is a type of cell death that is fundamentally distinct from degenerative death or necrosis in that it is an active process of gene-directed cellular self-destruction which in some instances, serves a biologically meaningful homeostatic function. Necrosis, in contrast, is cell death occurring as the result of severe injurious changes in the environment of infected cells. For a general review of apoptosis, see Tomei, L. D. and Cope, F. O. Apoptosis: The Molecular Basis of Cell Death (1991) Cold Spring Harbor Press, N.Y.; Tomei, L. D. and Cope, F. O. Apoptosis II: The Molecular Basis of Apoptosis in Disease (1994) Cold Spring Harbor Press, N.Y.; and Duvall and Wyllie (1986) Immun. Today 7(4):115-119.
Morphologically, apoptosis is characterized by the rapid condensation of the cell with preservation of membranes. Synchronistically with the compaction of chromatin, several biochemical changes occur in the cell. Nuclear DNA is cleaved at the linker regions between nucleosomes to produce fragments that are easily demonstrated by agarose gel electrophoresis wherein a characteristic ladder develops.
Numerous triggers for apoptosis have been identified that induce cell death. The Fas antigen (CD95/APO-1) is a member of the tumor necrosis factor (TNF) receptor superfamily. It is a transmembrane protein with wide tissue distribution. Fas triggers apoptosis upon activation when bound to its ligand or to agonistic anti-Fas antibodies. Cytotoxic T-lymphocytes activate Fas on target cells, inducing cytolysis. TNF also is known to induce apoptosis when cross-linked by its ligand or an agonist antibody.
In addition to being linked to the many biological processes identified above, apoptosis also occurs as a result of human immunodeficiency virus (HIV) infection of CD4.sup.+ T lymphocytes (T cells). Indeed, one of the major characteristics of AIDS is the gradual depletion of CD4.sup.+ T lymphocytes during the development of the disease. Several mechanisms, including apoptosis, have been suggested to be responsible for the CD4 depletion. The depletion of CD4.sup.+ T cells results in the impairment of the cellular immune response. It has been proposed that an inappropriate activation-induced T cell PCD causes the functional and numerical abnormalities of T.sub.H cells from HIV-infected patients, that leads to the near collapse of the patient's immune system. The mechanism by which the Fas antigen initiates the apoptotic cascade, and its various components, remains to be fully elucidated. However, this invention has identified several components of the apoptotic cascade and methods to modulate apoptosis.